Relation between genotype and phenotype in Swedish phenylketonuria and hyperphenylalaninemia patients

Phenylketonuria (PKU) and hyperphenylalaninemia (HPA) are caused mostly by an inherited (autosomal recessive) deficiency in hepatic phenylalanine hydroxylase (PAH) activity. More than 50 PAH mutations have ben reported. The goal of the present study was to examine the molecular basis for the clinical heterogeneity of Swedish PKU and HPA patients. Mutations were identified through allele-specific oligonucleotide hybridization or DNA sequencing on 128 of the 176 mutant alleles (73%). Three mutations (R408W, Y414C and IVS12) together accounted for 56% of all mutant alleles and ten relatively infrequent mutations were found on another 17% of all mutant alleles. Patients from 50 of the 88 families (57%) had identified mutations in both PAH genes and allowed use to compare the clinical effects of different combinations of PAH mutations. The in vitro activity of all of these mutations, including the newly identified G272X and L364, have been tested in a eukaryotic expression system. There was a strong relationship between the average in vitro PAH activity of the two mutant enzymes and both the phenylalanine tolerance and the neonatal pretreatment serum phenylalanine concentration. This confirms previous observations in Danish and German PKU patients that disease phenotype is a consequence of the nature of the mutations at the PAH locus and not significantly influenced by other loci. The sample population in the previous study did not, however, include mild HPA patients, and the observed correlation is thus restricted to severe and moderate mutant alleles. Since a comparatively high proportion of the Swedish patients were mildly affected, we have provided additional evidence that this correlation is valid throughout a continuous spectrum of clinical varieties. PAH genotyping could therefore help predict prognosis of a recently diagnosed PKU or HPA child.     

Rotational barrier of a molybdenum-molybdenum quadruple bond

The synthesis and characterization of molybdenum(II) porphyrin dimers containing unbridged metal-metal quadruple bonds are presented. Variable temperature 300 MHz ¹H NMR studies of meso-substituted derivatives provide novel solution evidence for both the existence of quadruple bonds and for a barrier to rotation about the metal-metal bonds in these complexes. The activation energy for this rotational process is 10.1 ± 0.5 kcal·mol^-1.     

Vision through cataracts

Contrast thresholds for a range of different spatial frequencies were compared with "acuity" tests for 10 subjects with uniocular senile cataract. The results indicate that the magnitude and extent of the intra-resolution limit abnormality vary dramatically in cataract subjects and that, for some subjects, vision is abnormal for objects of all sizes. This finding indicates that the present acuity evaluation of vision with cataracts is inadequate because, in some cases, it grossly overestimates the nature of the visual world of the cataract patient.     

Biological evaluation of Korean medicinal plants(III)

The extracts of sixty Korean plants were evaluated for their biological activities such as antitumor activities against Sarcoma 180, Leukemia SN-36 and Ehrlich ascites carcinoma, antimicrobial activities and behavioral observation in mice. The results are tabulated.     

Carbonic anhydrase IX expression, hypoxia, and prognosis in patients with uterine cervical carcinomas.

PURPOSE: Hypoxia is associated with adverse outcome for a number of solid tumors, including cervical carcinomas. Direct pO(2) measurement requires specialized equipment and expertise that is not generally available. Immunohistochemical measurement of intrinsic tissue markers of hypoxia is an alternative approach. Recent studies suggest that carbonic anhydrase IX (CA IX), which is regulated via hypoxia-inducible factor 1, is a useful intrinsic marker of tumor hypoxia. EXPERIMENTAL DESIGN: Biopsies were obtained from 110 patients with locally advanced cervical carcinoma treated with radiotherapy or chemoradiotherapy. Tissue sections were labeled using an immunofluorescence technique and CA IX expression in the viable tumor area measured using a semiautomated fluorescence image analysis technique. Results were compared with direct pO(2) values obtained using an Eppendorf probe and to patient outcome. Intratumoral heterogeneity of CA IX expression was examined in a subgroup of patient who underwent multiple biopsies. RESULTS: The median percentage of tumor area staining for CA IX was 3.56 (range, 0.01-58.85). CA IX staining did not correlate with the Eppendorf pO(2) measurements. Whereas the latter values were predictive of patient outcome, the CA IX levels were not. Measurement of CA IX in multiple biopsies indicated that intratumoral heterogeneity accounted for 41% of the total variance in the data set. CONCLUSIONS: In contrast to some recent studies, we did not find significant associations between CA IX expression and tumor pO(2) levels or patient outcome in locally advanced carcinomas of the cervix. Probable explanations relate to the problems of sampling error using single biopsies and the existence of biological factors other than hypoxia that influence CA IX levels.     

Interaction between the ACL graft and MCL in a combined ACL+MCL knee injury using a goat model

The optimal treatment for the MCL in the combined ACL and MCL-injured knee is still controversial. Therefore, we designed this study to examine the mechanical interaction between the ACL graft and the MCL in a goat model using a robotic/universal force-moment sensor testing system. The kinematics of intact, ACL-deficient, ACL-reconstructed, and ACL-reconstructed/ MCL-deficient knees, as well as the in situ forces in the ACL, ACL graft, and MCL were determined in response to two external loading conditions: 1) anterior tibial load of 67 N and 2) valgus moment of 5 N-m. With an anterior tibial load, anterior tibial translation in the ACL-deficient knee significantly increased from 2.0 and 2.2 mm to 15.7 and 18.1 mm at 30 degrees and 60 degrees of knee flexion, respectively. The in situ forces in the MCL also increased from 8 to 27 N at 60 degrees of knee flexion. ACL reconstruction reduced the anterior tibial translation to within 2 mm of the intact knee and significantly reduced the in situ force in the MCL to 17 N. However, in response to a valgus moment, the in situ forces in the ACL graft increased significantly by 34 N after transecting the MCL. These findings show that ACL deficiency can increase the in situ forces in the MCL while ACL reconstruction can reduce the in situ forces in the MCL in response to an anterior tibial load. On the other hand, the ACL graft is subjected to significantly higher in situ forces with MCL deficiency during an applied valgus moment. Therefore, the ACL-reconstructed knee with a combined ACL and MCL injury should be protected from high valgus moments during early healing to avoid excessive loading on the graft.     

Value of lying-down nystagmus in the lateralization of horizontal semicircular canal benign paroxysmal positional vertigo.

BACKGROUND: Horizontal canal benign paroxysmal positional vertigo is characterized by horizontal direction-changing nystagmus induced by lateral head turning in supine position. According to Ewald's second law, the direction of head turning that creates a stronger response represents the affected side in geotropic nystagmus and the healthy side in apogeotropic nystagmus. However, it may not always be possible to lateralize the involved ear only by comparing the intensity of the nystagmus. We studied the values of nystagmus induced by position change from sitting to supine in the lateralization of horizontal canal benign paroxysmal positional vertigo. METHODS: A retrospective study of 54 patients who had been diagnosed as having horizontal canal benign paroxysmal positional vertigo at the Dizziness Clinic of Seoul National University Bundang Hospital from May 2003 to February 2004 was performed. The directions of the nystagmus induced by lying down were compared with those determined by Ewald's second law. RESULTS: Of the 54 patients, 32 (20 apogeotropic and 12 geotropic) showed horizontal nystagmus induced by lying down. The nystagmus tended to be ipsilesional in apogeotropic patients (80%) and contralesional in their geotropic counterparts (75%). CONCLUSION: In horizontal canal benign paroxysmal positional vertigo, lying-down nystagmus mostly beats toward the involved ear in the apogeotropic type and directs to the healthy ear in the geotropic type. The direction of lying-down nystagmus may help lateralizing the involved ear in horizontal canal benign paroxysmal positional vertigo.     

YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma.

PURPOSE: YKL-40 is a secreted protein that has been reported to be overexpressed in epithelial cancers and gliomas, although its function is unknown. Previous data in a smaller sample set suggested that YKL-40 was a marker associated with a poorer clinical outcome and a genetically defined subgroup of glioblastoma. Here we test these findings in a larger series of patients with glioblastoma, and in particular, determine if tumor YKL-40 expression is associated with radiation response. EXPERIMENTAL DESIGN: Patients (n=147) with subtotal resections were studied for imaging-assessed changes in tumor size in serial studies following radiation therapy. An additional set (n=140) of glioblastoma patients who underwent a gross-total resection was tested to validate the survival association and extend them to patients with minimal residual disease. RESULTS: In the subtotal resection group, higher YKL-40 expression was significantly associated with poorer radiation response, shorter time to progression and shorter overall survival. The association of higher YKL-40 expression with poorer survival was validated in the gross-total resection group. In multivariate analysis with both groups combined (n = 287), YKL-40 was an independent predictor of survival after adjusting for patient age, performance status, and extent of resection. YKL-40 expression was also compared with genetically defined subsets of glioblastoma by assessing epidermal growth factor receptor amplification and loss at chromosome 10q, two of the common recurring aberrations in these tumors, using fluorescent in situ hybridization. YKL-40 was significantly associated with 10q loss. CONCLUSIONS: The findings implicate YKL-40 as an important marker of therapeutic response and genetic subtype in glioblastomas and suggest that it may play an oncogenic role in these tumors.     

Sodium Tetradecyl Sulphate Sclerotherapy for Lateral Malleolar Bursitis of the Ankle

BackgroundThe aim of this study was to evaluate clinical outcomes of sodium tetradecyl sulphate (STS) sclerotherapy for conservative treatment of lateral malleolar bursitis of the ankle.MethodsWe reviewed data from 20 consecutive patients (20 ankles) who underwent STS sclerotherapy between August 2018 and June 2019. After aspiration of fluid from the lateral malleolar bursal sac, 2 mL (20 mg) STS was injected into the sac. Clinical outcomes and side effects and complications were evaluated at 2 weeks, 3 months, 1 year, and 2 years after sclerotherapy. Responses to treatment were assessed according to degree of fluctuation, shrinkage of the bursal sac, and soft-tissue swelling. The 36-item short form survey (SF-36) was completed for each patient before and after therapy.ResultsComplete response was observed in 17 patients (85%), and partial response was observed in 3 patients (15%) after STS sclerotherapy. SF-36 physical component scores improved from 62.2 (interquartile range, 5.2) before therapy to 70.0 (interquartile range, 7.9) at last follow-up (p < 0.05). One patient (5%) experienced transient hyperpigmentation at the injection site. No major complications occurred.ConclusionsSTS sclerotherapy was an effective and safe treatment for patients with lateral malleolar bursitis of the ankle.